tbuckley/cabot-search huggingface dataset:
Closing the gap in childhood immunisation after the pandemic
Authors: Isabelle Munyangaju, Elisa López-Varela, Quique Bassat
Journal: BMJ (2023)

Childhood immunisations are among the most cost effective, equitable, and successful interventions of all times.The World Health Organization's expanded programme on immunisation has ensured that routine childhood immunisations are available in every country, and vaccination is believed to save around three million lives annually. 1Eligible low and middle income countries have been supported by Gavi (the Vaccine Alliance) and Unicef to improve access to new and underused vaccines.Vaccination coverage increased substantially between 2000 and 2019, averting about 37 million deaths globally during that period.The global coverage of DTP3 (three doses of the combined diphtheria, pertussis, and tetanus vaccine), third polio dose, and first measles dose was 84%-86% globally by 2019, and coverage of the second dose of measles vaccine increased from 42% to 71% from 2010 to 2019.Coverage of more recently recommended vaccines such as rotavirus, pneumococcal conjugate, rubella, and hepatitis B also increased.
Multi-omics analysis identifies drivers of protein phosphorylation
Authors: Tian Zhang, Gregory R. Keele, Isabela Gerdes Gyuricza, Matthew Vincent, Catherine Brunton, Timothy A. Bell, Pablo Hock, Ginger D. Shaw, Steven C. Munger, Fernando Pardo-Manuel de Villena, Martin T. Ferris, Joao A. Paulo, Steven P. Gygi, Gary A. Churchill
Journal: Genome biology (2023)

Abstract Background Phosphorylation of proteins is a key step in the regulation of many cellular processes including activation of enzymes and signaling cascades. The abundance of a phosphorylated peptide (phosphopeptide) is determined by the abundance of its parent protein and the proportion of target sites that are phosphorylated. Results We quantified phosphopeptides, proteins, and transcripts in heart, liver, and kidney tissue samples of mice from 58 strains of the Collaborative Cross strain panel. We mapped ~700 phosphorylation quantitative trait loci (phQTL) across the three tissues and applied genetic mediation analysis to identify causal drivers of phosphorylation. We identified kinases, phosphatases, cytokines, and other factors, including both known and potentially novel interactions between target proteins and genes that regulate site-specific phosphorylation. Our analysis highlights multiple targets of pyruvate dehydrogenase kinase 1 (PDK1), a regulator of mitochondrial function that shows reduced activity in the NZO/HILtJ mouse, a polygenic model of obesity and type 2 diabetes. Conclusions Together, this integrative multi-omics analysis in genetically diverse CC strains provides a powerful tool to identify regulators of protein phosphorylation. The data generated in this study provides a resource for further exploration.
RETRACTED ARTICLE: AMLnet, A deep-learning pipeline for the differential diagnosis of acute myeloid leukemia from bone marrow smears
Authors: Zebin Yu, Jianhu Li, Xiang Wen, Yingli Han, Penglei Jiang, Meng Zhu, Minmin Wang, Xiangli Gao, Dan Shen, Ting Zhang, Shuqi Zhao, Yijing Zhu, Jixiang Tong, Shuchong Yuan, HongHu Zhu, He Huang, Pengxu Qian
Journal: Journal of Hematology & Oncology (2023)

Abstract Acute myeloid leukemia (AML) is a deadly hematological malignancy. Cellular morphology detection of bone marrow smears based on the French–American–British (FAB) classification system remains an essential criterion in the diagnosis of hematological malignancies. However, the diagnosis and discrimination of distinct FAB subtypes of AML obtained from bone marrow smear images are tedious and time-consuming. In addition, there is considerable variation within and among pathologists, particularly in rural areas, where pathologists may not have relevant expertise. Here, we established a comprehensive database encompassing 8245 bone marrow smear images from 651 patients based on a retrospective dual-center study between 2010 and 2021 for the purpose of training and testing. Furthermore, we developed AMLnet, a deep-learning pipeline based on bone marrow smear images, that can discriminate not only between AML patients and healthy individuals but also accurately identify various AML subtypes. AMLnet achieved an AUC of 0.885 at the image level and 0.921 at the patient level in distinguishing nine AML subtypes on the test dataset. Furthermore, AMLnet outperformed junior human experts and was comparable to senior experts on the test dataset at the patient level. Finally, we provided an interactive demo website to visualize the saliency maps and the results of AMLnet for aiding pathologists’ diagnosis. Collectively, AMLnet has the potential to serve as a fast prescreening and decision support tool for cytomorphological pathologists, especially in areas where pathologists are overburdened by medical demands as well as in rural areas where medical resources are scarce.
Biomarkers for staging fibrosis and non-alcoholic steatohepatitis in non-alcoholic fatty liver disease (the LITMUS project): a comparative diagnostic accuracy study
Authors: Yasaman Vali, Jenny Lee, Jerome Boursier, Salvatore Petta, Kristy Wonders, Dina Tiniakos, Pierre Bedossa, Andreas Geier, Sven Francque, Mike Allison, Georgios Papatheodoridis, Helena Cortez-Pinto, Raluca Pais, Jean-Francois Dufour, Diana Julie Leeming, Stephen A Harrison, Yu Chen, Jeremy F Cobbold, Michael Pavlides, Adriaan G Holleboom, Hannele Yki-Jarvinen, Javier Crespo, Morten Karsdal, Rachel Ostroff, Mohammad Hadi Zafarmand, Richard Torstenson, Kevin Duffin, Carla Yunis, Clifford Brass, Mattias Ekstedt, Guruprasad P Aithal, Jörn M Schattenberg, Elisabetta Bugianesi, Manuel Romero-Gomez, Vlad Ratziu, Quentin M Anstee, Patrick M Bossuyt
Journal: The Lancet. Gastroenterology & hepatology (2023)
The power of 2,6-diaminopurine in correcting UGA nonsense codons in CFTR mRNA
Authors: Luísa Romão
Journal: Molecular Therapy (2023)

Nonsense mutations are the molecular basis for ∼11% of all human genetic disorders.1 These mutations introduce an in-frame premature translation-termination codon (PTC) into the protein-coding gene sequence. mRNAs carrying a PTC are, in general, recognized and degraded by the nonsense-mediated mRNA decay (NMD) machinery to prevent the expression of truncated proteins that could be nonfunctional or have gain of function or dominant-negative effects.2,3,4 Different therapeutic strategies have been developed to rescue and correct the expression of PTC-carrying genes,5 such as PTC readthrough, also called nonsense suppression, therapy.
Autoimmune manifestations in VEXAS: Opportunities for integration and pitfalls to interpretation
Authors: Alessandro Bruno, Carmelo Gurnari, Tobias Alexander, John A. Snowden, Raffaella Greco
Journal: Journal of Allergy and Clinical Immunology (2023)

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a novel entity manifesting with a multiplicity of clinical features. Somatic mutations of the UBA1 gene in hematopoietic stem cells constitute the genetic basis of VEXAS. As an X-linked disorder, most cases occur in men, classically developing symptoms during the fifth to sixth decade of life. Considering its multidisciplinary nature involving numerous branches of internal medicine, VEXAS has elicited a wide medical interest and several medical conditions have been associated with this disease. Even so, its recognition in everyday clinical practice is not necessarily straightforward. Close collaboration between different medical specialists is mandatory. Patients with VEXAS may manifest a range of features from manageable cytopenias to disabling and life-threatening autoimmune phenomena with limited responses to therapy, with the potential for progression to hematological malignancies. Diagnostic and treatment guidelines are exploratory and include a range of rheumatological and supportive care treatments. Allogeneic hematopoietic stem cell transplantation is potentially curative, but its risks are significant and its position in the treatment algorithm is yet to be defined. Herein, we present the variegated manifestations of VEXAS, provide practice criteria for diagnostic testing of UBA1, and discuss potential treatment options, including allogeneic hematopoietic stem cell transplantation, current evidence, and future directions.
Dual targeting of CD19 and CD22 against B-ALL using a novel high-sensitivity aCD22 CAR
Authors: Evangelia Kokalaki, Biao Ma, Mathieu Ferrari, Thomas Grothier, Warren Hazelton, Somayya Manzoor, Eren Costu, Julia Taylor, Anna Bulek, Saket Srivastava, Isaac Gannon, Ram Jha, Rosalind Gealy, Lukas Stanczuk, Tatiana Rizou, Mathew Robson, Mohamed El-Kholy, Vania Baldan, Matteo Righi, James Sillibourne, Simon Thomas, Shimobi Onuoha, Shaun Cordoba, Martin Pule
Journal: Molecular Therapy (2023)

CAR T cells recognizing CD19 effectively treat relapsed and refractory B-ALL and DLBCL. However, CD19 loss is a frequent cause of relapse. Simultaneously targeting a second antigen, CD22, may decrease antigen escape, but is challenging: its density is approximately 10-fold less than CD19, and its large structure may hamper immune synapse formation. The characteristics of the optimal CD22 CAR are underexplored. We generated 12 distinct CD22 antibodies and tested CARs derived from them to identify a CAR based on the novel 9A8 antibody, which was sensitive to low CD22 density and lacked tonic signaling. We found no correlation between affinity or membrane proximity of recognition epitope within Ig domains 3–6 of CD22 with CART function. The optimal strategy for CD19/CD22 CART co-targeting is undetermined. Co-administration of CD19 and CD22 CARs is costly; single CARs targeting CD19 and CD22 are challenging to construct. The co-expression of two CARs has previously been achieved using bicistronic vectors. Here, we generated a dual CART product by co-transduction with 9A8-41BBζ and CAT-41BBζ (obe-cel), the previously described CD19 CAR. CAT/9A8 CART eliminated single- and double-positive target cells in vitro and eliminated CD19- tumors in vivo. CAT/9A8 CART is being tested in a phase I clinical study (NCT02443831). CAR T cells recognizing CD19 effectively treat relapsed and refractory B-ALL and DLBCL. However, CD19 loss is a frequent cause of relapse. Simultaneously targeting a second antigen, CD22, may decrease antigen escape, but is challenging: its density is approximately 10-fold less than CD19, and its large structure may hamper immune synapse formation. The characteristics of the optimal CD22 CAR are underexplored. We generated 12 distinct CD22 antibodies and tested CARs derived from them to identify a CAR based on the novel 9A8 antibody, which was sensitive to low CD22 density and lacked tonic signaling. We found no correlation between affinity or membrane proximity of recognition epitope within Ig domains 3–6 of CD22 with CART function. The optimal strategy for CD19/CD22 CART co-targeting is undetermined. Co-administration of CD19 and CD22 CARs is costly; single CARs targeting CD19 and CD22 are challenging to construct. The co-expression of two CARs has previously been achieved using bicistronic vectors. Here, we generated a dual CART product by co-transduction with 9A8-41BBζ and CAT-41BBζ (obe-cel), the previously described CD19 CAR. CAT/9A8 CART eliminated single- and double-positive target cells in vitro and eliminated CD19- tumors in vivo. CAT/9A8 CART is being tested in a phase I clinical study (NCT02443831).
Classification of Tumor Immune Microenvironment According to Programmed Death-Ligand 1 Expression and Immune Infiltration Predicts Response to Immunotherapy Plus Chemotherapy in Advanced Patients With NSCLC
Authors: Dongchen Sun, Jiaqing Liu, Huaqiang Zhou, Mengting Shi, Jiya Sun, Shen Zhao, Gang Chen, Yaxiong Zhang, Ting Zhou, Yuxiang Ma, Yuanyuan Zhao, Wenfeng Fang, Hongyun Zhao, Yan Huang, Yunpeng Yang, Li Zhang
Journal: Journal of Thoracic Oncology (2023)

According to mechanisms of adaptive immune resistance, tumor immune microenvironment (TIME) is classified into four types: (1) programmed death-ligand 1 (PD-L1)-negative and tumor-infiltrating lymphocyte (TIL)-negative (type I); (2) PD-L1-positive and TIL-positive (type II); (3) PD-L1-negative and TIL-positive (type III); and (4) PD-L1-positive and TIL-negative (type IV). However, the relationship between the TIME classification model and immunotherapy efficacy has not been validated by any large-scale randomized controlled clinical trial among patients with advanced NSCLC.On the basis of RNA-sequencing and immunohistochemistry data from the ORIENT-11 study, we optimized the TIME classification model and evaluated its predictive value for the efficacy of immunotherapy plus chemotherapy.PD-L1 mRNA expression and immune score calculated by the ESTIMATE method were the strongest predictors for the efficacy of immunotherapy plus chemotherapy. Therefore, they were determined as the optimized definition of the TIME classification system. When compared between combination therapy and chemotherapy alone, only the type II subpopulation with high immune score and high PD-L1 mRNA expression was significantly associated with improved progression-free survival (PFS) (hazard ratio = 0.12, 95% confidence interval: 0.06-0.25, p < 0.001) and overall survival (hazard ratio = 0.27, 95% confidence interval: 0.13-0.55, p < 0.001). In the combination group, the type II subpopulation had a much longer survival time, not even reaching the median PFS or overall survival, but the other three subpopulations were susceptible to having similar PFS. In the chemotherapy group, there was no marked association between survival outcomes and TIME subtypes.Only patients with both high PD-L1 expression and high immune infiltration could benefit from chemotherapy plus immunotherapy in first-line treatment of advanced NSCLC. For patients lacking either PD-L1 expression or immune infiltration, chemotherapy alone might be a better treatment option to avoid unnecessary toxicities and financial burdens.
Increased risk of cutaneous immune-related adverse events in patients treated with talimogene laherparepvec and immune checkpoint inhibitors: A multi-hospital cohort study
Authors: Bonnie W. Leung, Guihong Wan, Nga Nguyen, Hannah Rashdan, Shijia Zhang, Wenxin Chen, Sonia Cohen, Genevieve M. Boland, Ryan J. Sullivan, Riley M. Fadden, Howard L. Kaufman, Shawn G. Kwatra, Nicole R. LeBoeuf, Yevgeniy R. Semenov
Journal: Journal of the American Academy of Dermatology (2023)
Pseudoknot-targeting Cas13b combats SARS-CoV-2 infection by suppressing viral replication
Authors: Daseuli Yu, Hee-Jeong Han, Jeonghye Yu, Jihye Kim, Gun-Hee Lee, Ju-Hee Yang, Byeong-Min Song, Dongseob Tark, Byeong-Sun Choi, Sang-Min Kang, Won Do Heo
Journal: Molecular Therapy (2023)

CRISPR-Cas13-mediated viral genome targeting is a novel strategy for defending against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Here, we generated mRNA-encoded Cas13b targeting the open reading frame 1b (ORF1b) region to effectively degrade the RNA-dependent RNA polymerase gene. Of the 12 designed CRISPR RNAs (crRNAs), those targeting the pseudoknot site upstream of ORF1b were found to be the most effective in suppressing SARS-CoV-2 propagation. Pseudoknot-targeting Cas13b reduced expression of the spike protein and attenuated viral replication by 99%. It also inhibited the replication of multiple SARS-CoV-2 variants, exhibiting broad potency. We validated the therapeutic efficacy of this system in SARS-CoV-2-infected hACE2 transgenic mice, demonstrating that crRNA treatment significantly reduced viral titers. Our findings suggest that the pseudoknot region is a strategic site for targeted genomic degradation of SARS-CoV-2. Hence, pseudoknot-targeting Cas13b could be a breakthrough therapy for overcoming infections by SARS-CoV-2 or other RNA viruses.
RAS degraders: The new frontier for RAS-driven cancers
Authors: Taylor E. Escher, Karla J.F. Satchell
Journal: Molecular Therapy (2023)

The function and significance of RAS proteins in cancer have been widely studied for decades. In 2013, the National Cancer Institute established the RAS Initiative to explore innovative approaches for attacking the proteins encoded by mutant forms of RAS genes and to create effective therapies for RAS-driven cancers. This initiative spurred researchers to develop novel approaches and to discover small molecules targeting this protein that was at one time termed "undruggable." More recently, advanced efforts in RAS degraders including PROTACs, linker-based degraders, and direct proteolysis degraders have been explored as novel strategies to target RAS for cancer treatment. These RAS degraders present new opportunities for RAS therapies and may prove fruitful in understanding basic cell biology. Novel delivery strategies will further enhance the efficacy of these therapeutics. In this review, we summarize recent efforts to develop RAS degraders, including PROTACs and E3 adaptor and ligase fusions as cancer therapies. This review also details the direct RAS protease degrader, RAS/RAP1-specific endopeptidase that directly and specifically cleaves RAS.
D-1553 (Garsorasib), a Potent and Selective Inhibitor of KRASG12C in Patients With NSCLC: Phase 1 Study Results
Authors: Ziming Li, Zhengbo Song, Yanqiu Zhao, Pingli Wang, Liyan Jiang, Yi Gong, Jianying Zhou, Hong Jian, Xiaorong Dong, Wu Zhuang, Shundong Cang, Nong Yang, Jian Fang, Jianhua Shi, Junguo Lu, Rui Ma, Ping Wu, Yingqian Zhang, Mengmeng Song, Chun-Wei Xu, Zhe Shi, Ling Zhang, Yaolin Wang, Xicheng Wang, Yiping Zhang, Shun Lu
Journal: Journal of Thoracic Oncology (2023)
The endoplasmic reticulum stress and unfolded protein response in Alzheimer’s disease: A calcium dyshomeostasis perspective
Authors: Dmitry Lim, Laura Tapella, Giulia Dematteis, Armando A. Genazzani, Marco Corazzari, Alexei Verkhratsky
Journal: Ageing Research Reviews (2023)

Protein misfolding is prominent in early cellular pathology of Alzheimer's disease (AD), implicating pathophysiological significance of endoplasmic reticulum stress/unfolded protein response (ER stress/UPR) and highlighting it as a target for drug development. Experimental data from animal AD models and observations on human specimens are, however, inconsistent. ER stress and associated UPR are readily observed in in vitro AD cellular models and in some AD model animals. In the human brain, components and markers of ER stress as well as UPR transducers are observed at Braak stages III-VI associated with severe neuropathology and neuronal death. The picture, however, is further complicated by the brain region- and cell type-specificity of the AD-related pathology. Terms 'disturbed' or 'non-canonical' ER stress/UPR were used to describe the discrepancies between experimental data and the classic ER stress/UPR cascade. Here we discuss possible 'disturbing' or 'interfering' factors which may modify ER stress/UPR in the early AD pathogenesis. We focus on the dysregulation of the ER Ca2+ homeostasis, store-operated Ca2+ entry, and the interaction between the ER and mitochondria. We suggest that a detailed study of the CNS cell type-specific alterations of Ca2+ homeostasis in early AD may deepen our understanding of AD-related dysproteostasis.
An updated atlas of antibody evasion by SARS-CoV-2 Omicron sub-variants including BQ.1.1 and XBB
Authors: Qingwen He, Lili Wu, Zepeng Xu, Xiaoyun Wang, Yufeng Xie, Yan Chai, Anqi Zheng, Jianjie Zhou, Shitong Qiao, Min Huang, Guijun Shang, Xin Zhao, Youjun Feng, Jianxun Qi, George Fu Gao, Qihui Wang
Journal: Cell Reports Medicine (2023)

Emerging Omicron sub-variants are causing global concerns, and their immune evasion should be monitored continuously. We previously evaluated the escape of Omicron BA.1, BA.1.1, BA.2, and BA.3 from an atlas of 50 monoclonal antibodies (mAbs), covering seven epitope classes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor-binding domain (RBD). Here, we update the atlas of totally 77 mAbs against emerging sub-variants including BQ.1.1 and XBB and find that BA.4/5, BQ.1.1, and XBB display further evasion. Besides, investigation into the correlation of binding and neutralization of mAbs reveals the important role of antigenic conformation in mAb functioning. Moreover, the complex structures of BA.2 RBD/BD-604/S304 and BA.4/5 RBD/BD-604/S304/S309 further elucidate the molecular mechanism of antibody evasion by these sub-variants. By focusing on the identified broadly potent mAbs, we find a general hotspot epitope on the RBD, which could guide the design of vaccines and calls for new broad-spectrum countermeasures against COVID-19.
PDAtt-Unet: Pyramid Dual-Decoder Attention Unet for Covid-19 infection segmentation from CT-scans
Authors: Fares Bougourzi, Cosimo Distante, Fadi Dornaika, Abdelmalik Taleb-Ahmed
Journal: Medical Image Analysis (2023)

Since the emergence of the Covid-19 pandemic in late 2019, medical imaging has been widely used to analyze this disease. Indeed, CT-scans of the lungs can help diagnose, detect, and quantify Covid-19 infection. In this paper, we address the segmentation of Covid-19 infection from CT-scans. To improve the performance of the Att-Unet architecture and maximize the use of the Attention Gate, we propose the PAtt-Unet and DAtt-Unet architectures. PAtt-Unet aims to exploit the input pyramids to preserve the spatial awareness in all of the encoder layers. On the other hand, DAtt-Unet is designed to guide the segmentation of Covid-19 infection inside the lung lobes. We also propose to combine these two architectures into a single one, which we refer to as PDAtt-Unet. To overcome the blurry boundary pixels segmentation of Covid-19 infection, we propose a hybrid loss function. The proposed architectures were tested on four datasets with two evaluation scenarios (intra and cross datasets). Experimental results showed that both PAtt-Unet and DAtt-Unet improve the performance of Att-Unet in segmenting Covid-19 infections. Moreover, the combination architecture PDAtt-Unet led to further improvement. To Compare with other methods, three baseline segmentation architectures (Unet, Unet++, and Att-Unet) and three state-of-the-art architectures (InfNet, SCOATNet, and nCoVSegNet) were tested. The comparison showed the superiority of the proposed PDAtt-Unet trained with the proposed hybrid loss (PDEAtt-Unet) over all other methods. Moreover, PDEAtt-Unet is able to overcome various challenges in segmenting Covid-19 infections in four datasets and two evaluation scenarios.
When cleaning facilitates cluttering – genome editing in ciliates
Authors: Brandon Kwee Boon Seah, Estienne Carl Swart
Journal: Trends in Genetics (2023)

Many organisms remove DNA from their genomes during development. This has foremost been characterized as a means of defending genomes against mobile elements. However, genome editing actually hides such elements from purifying selection, with the survivors evolving approximately neutrally, 'cluttering' the germline genome, enabling it to enlarge over time.
Publisher Correction: Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial
Authors: Thomas Powles, Mark Kockx, Alejo Rodriguez-Vida, Ignacio Duran, Simon J. Crabb, Michiel S. Van Der Heijden, Bernadett Szabados, Albert Font Pous, Gwenaelle Gravis, Urbano Anido Herranz, Andrew Protheroe, Alain Ravaud, Denis Maillet, Maria Jose Mendez, Cristina Suarez, Mark Linch, Aaron Prendergast, Pieter-Jan van Dam, Diana Stanoeva, Sofie Daelemans, Sanjeev Mariathasan, Joy S. Tea, Kelly Mousa, Romain Banchereau, Daniel Castellano
Journal: Nature Medicine (2023)
Reply to the comment of Gallardo et al to “Challenges and limitations of teledermatology for skin and soft-tissue infections: A real-world study of an expert center”
Authors: Romain Salle, Charbel Skayem, Camille Hua, Olivier Chosidow, Tu-Anh Duong
Journal: Journal of the American Academy of Dermatology (2023)

Reply to the comment of Gallardo et al to ''Challenges and limitations of teledermatology for